SPLA2 hydrolysable liposomes with improved storage stability

Abstract

The present invention provides a composition comprising a sPLA2 hydrolysable liposome, an exterior solution, and an interior solution within the liposome, —wherein the concentration of osmolytes is higher in the interior solution than in the exterior solution. The composition improves storage stability of sPLA2 hydrolysable liposomes, in particular at when stored at 2-8 degrees Celsius. The liposome preferably encapsulates cisplatin. The invention also provides methods of preparing the composition of the invention.

The invention claimed is: 
     
       1. A pharmaceutical composition comprising:
 (a) a secretory phospholipase A 2  (sPLA 2 ) hydrolysable liposome comprising distearoyl phosphatidyl glycerol (DSPG) in an amount of 20% to 45% (mol/mol), distearoyl phosphatidyl choline (DSPC) in an amount of 40% to 75% (mol/mol), [poly(ethylene glycol)]-distearoyl phosphatidyl ethanolamine (DSPE-PEG) in an amount of 3% to 6% (mol/mol), less than 1% cholesterol, and cisplatin encapsulated in the liposome as a therapeutic agent, 
 (b) an exterior solution, and 
 (c) an interior solution within the liposome, 
 wherein a difference in osmolyte concentration between the interior solution and the exterior solution is greater than 200 mOsm, wherein the difference in osmolyte concentration is the exterior solution osmolyte concentration subtracted from the interior solution osmolyte concentration. 
 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the only therapeutic agent is cisplatin. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein the difference in osmolyte concentration between the interior solution and the exterior solution is between 200 mOsm and 600 mOsm. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein the difference in osmolyte concentration between the interior solution and the exterior solution is between 280 mOsm and 320 mOsm. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein the difference in osmolyte concentration between the interior solution and the exterior solution is at least 275 mOsm. 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein the interior solution comprises NaCl or KCl at a concentration between 0.2 to 2.5% w/w. 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein the exterior solution comprises NaCl or KCl at a concentration between 0.2 to 2.5% w/w. 
     
     
       8. The pharmaceutical composition of  claim 1 , wherein the interior solution and the exterior solution are selected from the group consisting of:
 (a) Interior solution of 0.8% to 1.0% NaCl and 9% to 11% sucrose and exterior solution of 8 mM to 12 mM phosphate buffer (pH 6.5) and 9% to 11% sucrose, 
 (b) Interior solution of 1.6% to 2.0% NaCl and exterior solution of 8 mM to 12 mM phosphate buffer (pH 6.5) and 9% to 11% sucrose, 
 (c) Interior solution of 0.8% to 1.0% NaCl and 9% to 11% sucrose and exterior solution of 0.35% to 0.55% NaCl and 4% to 6% sucrose, and 
 (d) Interior solution of 0.8% to 1.0% NaCl and 9% to 11% sucrose and exterior solution of 8 mM to 12 mM phosphate buffer (pH 6.5) and 0.8% to 1.0% NaCl. 
 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein the liposome comprises an additional therapeutic agent. 
     
     
       10. The pharmaceutical composition of  claim 1 , wherein the liposome comprises DSPG in an amount of 25% (mol/mol), DSPC in an amount of 70% (mol/mol), DSPE-PEG in an amount of 5% (mol/mol), and less than 1% cholesterol. 
     
     
       11. The pharmaceutical composition comprising more than one of said liposome of  claim 1 . 
     
     
       12. The pharmaceutical composition of  claim 1 , wherein leakage of cisplatin from the liposome is reduced relative to the liposome having a difference in osmolyte concentration between the interior solution and the exterior solution of less than 200 mOsm.